2. Academic Validation
  3. Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases

Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases

  • Cell Rep Med. 2026 Feb 17;7(2):102580. doi: 10.1016/j.xcrm.2025.102580.
Xianghui Dong 1,  Xiaotian Zhao 1,  Jinxin Gao 1,  Longyu Bo 1,  Caiping Li 1,  Zhichao Kong 1,  Weiyi Sun 1,  Xinxin Xu 1,  Zhanyan Liu 1,  Qirui Xiu 1,  Ying Zhi 2,  Jingzhao Lou 1,  Na Li 3,  Yudong Song 4,  Xinyi Jiang 5,  Kun Zhao 6
Affiliations

Affiliations

  • 1 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
  • 2 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China.
  • 3 College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan 250014, P.R. China. Electronic address: [email protected].
  • 4 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 5 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 6 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: [email protected].
PMID: 41616764 DOI: 10.1016/j.xcrm.2025.102580
Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2), a critical sensor of cell debris, regulates macrophage efferocytosis to maintain tissue immune homeostasis. However, inflammatory mediators upregulate the sheddase ADAM17, leading to TREM2 cleavage, which impairs apoptotic cell clearance and exacerbates inflammation. We here report a synthetic cleavage-resistant TREM2 (CRT) to boost TREM2-dependent efferocytosis and alleviate inflammation associated with aberrantly accumulated apoptotic cells. CRT integrates the ligand-binding domain of TREM2 with its intracellular signaling adaptor DAP12 via a custom-engineered stalk and transmembrane segment. Our data demonstrate that CRT amplifies TREM2 signaling even in the presence of ADAM17. Customized lipid nanoparticles efficiently introduce CRT mRNA into macrophages, generating CRT-engineered macrophages (CRT-Ms) in situ. CRT-Ms effectively reduce apoptotic cell burden and alleviate inflammation in mouse models of metabolic-dysfunction-associated steatohepatitis and atherosclerosis. In sum, our findings establish that CRT strengthens TREM2-mediated macrophage efferocytosis and mitigates inflammation, with broad potential for apoptotic-cell-associated diseases.

Keywords

TREM2; efferocytosis; inflammation; lipid nanoparticles; synthetic receptor engineering.

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